Imbalance of gut Bacteroides and Prevotella contributes to memory decline in ovariectomized mice fed with high-fat diet

Abstract

The rates of incidence and progression of Alzheimer’s disease (AD) vary significantly among post-menopausal women. However, the mechanisms that underlie this phenomenon remain obscure. Here, we established the high-fat diet-fed ovariectomized (OVXHF) mouse model and observed significant memory deficits in this model. Using 16S rDNA sequencing, we found that OVXHF mice displayed higher biodiversity and a distinct gut microbiome composition compared with normal chow-fed mice. Functional analysis further revealed that genes associated with the iron complex transport system and ATP-binding cassette are differentially expressed in OVXHF mice. Moreover, normal fecal microbiota transplantation (FMT) successfully restored the cognitive impairments in OVXHF mice through rebalancing the gut microbiota. In particular, the Bacteroides-to-Prevotella ratio was significantly increased in OVXHF mice but rescued by FMT. Altogether, these results suggest that an imbalance between Bacteroides and Prevotella in the gut microbiota accelerates the process of cognitive dysfunction in postmenopausal women on a high-fat diet.

Keywords

Estrogen deficiency / High-fat diet / Cognition decline / Gut microbiome / Bacteroides-Prevotella imbalance

Funding

This work was funded by the National Science and Technology Innovation 2030—Major Program of “Brain Science and Brain-Like Research” (2022ZD0211804 to J, A.).

Conflict of interest

Jing Ai is an Editorial Board Member of this journal but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

References

[1] Garre-Olmo J. Epidemiology of Alzheimer’s disease and other dementias. Rev Neurol. 2018; 66(11):377-386.

[2] Uddin MS, Mamun AA, Takeda S, Sarwar S, Begum M. Analyzing the chance of developing dementia among geriatric people: A cross-sectional pilot study in Bangladesh. Psychogeriatrics. 2019; 19(2):87-94. doi: 10.1111/psyg.12368

[3] Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology. 2013; 80(19):1778-1783. doi: 10.1212/WNL.0b013e31828726f5

[4] Hojo Y, Murakami G, Mukai H, et al. Estrogen synthesis in the brain--role in synaptic plasticity and memory. Mol Cell Endocrinol. 2008; 290(1-2):31-43. doi: 10.1016/j.mce.2008.04.017

[5] Mosconi L, Rahman A. Increased Alzheimer’s risk during the menopause transition: A 3-year longitudinal brain imaging study. PLoS One. 2018; 13(12):e0207885. doi: 10.1371/journal.pone.0207885

[6] Dumas JA, Kutz AM, Naylor MR, Johnson JV, Newhouse PA. Increased memory load-related frontal activation after estradiol treatment in postmenopausal women. Horm Behav. 2010; 58(5):929-935. doi: 10.1016/j.yhbeh.2010.09.003

[7] Kohama SG, Renner L, Landauer N, et al. Effect of ovarian hormone therapy on cognition in the aged female rhesus macaque. J Neurosci. 2016; 36(40):10416-10424. doi: 10.1523/JNEUROSCI.0909-16.2016

[8] Hao J, Rapp PR, Janssen WGM, et al. Interactive effects of age and estrogen on cognition and pyramidal neurons in monkey prefrontal cortex. Proc Natl Acad Sci U S A. 2007; 104(27):11465-11470. doi: 10.1073/pnas.0704757104

[9] Henderson VW. Alzheimer’s disease: Review of hormone therapy trials and implications for treatment and prevention after menopause. J Steroid Biochem Mol Biol. 2014; 142:99-106. doi: 10.1016/j.jsbmb.2013.05.010

[10] Baxter MG, Roberts MT, Gee NA, Lasley BL, Morrison JH, Rapp PR. Multiple clinically relevant hormone therapy regimens fail to improve cognitive function in aged ovariectomized rhesus monkeys. Neurobiol Aging. 2013; 34(7):1882-1890. doi: 10.1016/j.neurobiolaging.2012.12.017

[11] Gill SS, Seitz DP. Lifestyles and cognitive health: What older individuals can do to optimize cognitive outcomes. JAMA. 2015; 314(8):774-775. doi: 10.1001/jama.2015.9526

[12] Bach-Faig A, Berry EM, Lairon D, et al. Mediterranean diet pyramid today. Science and cultural updates. Public Health Nutr. 2011; 14(12a):2274-2284. doi: 10.1017/s1368980011002515

[13] Lourida I, Soni M, Thompson-Coon J, et al. Mediterranean diet, cognitive function, and dementia: A systematic review. Epidemiology. 2013; 24(4):479-489. doi: 10.1097/EDE.0b013e3182944410

[14] Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, Aggarwal NT. MIND diet associated with reduced incidence of Alzheimer’s disease. Alzheimers Dement. 2015; 11(9):1007-1014. doi: 10.1016/j.jalz.2014.11.009

[15] Omar SH. Mediterranean and MIND Diets containing olive biophenols reduces the prevalence of Alzheimer’s disease. Int J Mol Sci. 2019; 20(11):2797. doi: 10.3390/ijms20112797

[16] Gardener SL, Rainey-Smith SR, Barnes MB, et al. Dietary patterns and cognitive decline in an Australian study of ageing. Mol Psychiatry. 2015; 20(7):860-866. doi: 10.1038/mp.2014.79

[17] Shakersain B, Santoni G, Larsson SC, et al. Prudent diet may attenuate the adverse effects of Western diet on cognitive decline. Alzheimers Dement. 2016; 12(2):100-109. doi: 10.1016/j.jalz.2015.08.002

[18] Kim Y, Koh I, Rho M. Deciphering the human microbiome using next-generation sequencing data and bioinformatics approaches. Methods. 2015;79-80:52-59. doi: 10.1016/j.ymeth.2014.10.022

[19] Wang WL, Xu SY, Ren ZG, Tao L, Jiang JW, Zheng SS. Application of metagenomics in the human gut microbiome. World J Gastroenterol. 2015; 21(3):803-814. doi: 10.3748/wjg.v21.i3.803

[20] Long-Smith C, O’Riordan KJ, Clarke G, Stanton C, Dinan TG, Cryan JF. Microbiota-gut-brain axis: New therapeutic opportunities. Annu Rev Pharmacol Toxicol. 2020;60:477-502. doi: 10.1146/annurev-pharmtox-010919-023628

[21] Morais LH, Schreiber HL 4^th, Mazmanian SK. The gut microbiota-brain axis in behaviour and brain disorders. Nat Rev Microbiol. 2021; 19(4):241-255. doi: 10.1038/s41579-020-00460-0

[22] Zmora N, Suez J, Elinav E. You are what you eat: Diet, health and the gut microbiota. Nat Rev Gastroenterol Hepatol. 2019; 16(1):35-56. doi: 10.1038/s41575-018-0061-2

[23] Amar J, Burcelin R, Ruidavets JB, et al. Energy intake is associated with endotoxemia in apparently healthy men. Am J Clin Nutr. 2008; 87(5):1219-1223. doi: 10.1093/ajcn/87.5.1219

[24] Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007; 56(7):1761-1772. doi: 10.2337/db06-1491

[25] Caesar R, Tremaroli V, Kovatcheva-Datchary P, Cani PD, Bäckhed F. Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling. Cell Metab. 2015; 22(4):658-668. doi: 10.1016/j.cmet.2015.07.026

[26] Pitts MW. Barnes maze procedure for spatial learning and memory in mice. Bio Protoc. 2018; 8(5):e2744. doi: 10.21769/bioprotoc.2744

[27] Tanila H, Sipilä P, Shapiro M, Eichenbaum H. Brain aging: Impaired coding of novel environmental cues. J Neurosci. 1997; 17(13):5167-5174. doi: 10.1523/jneurosci.17-13-05167.1997

[28] Leger M, Quiedeville A, Bouet V, et al. Object recognition test in mice. Nat Protoc. 2013; 8(12):2531-2537. doi: 10.1038/nprot.2013.155

[29] Zhu H, Wang N, Yao L, et al. Moderate UV exposure enhances learning and memory by promoting a novel glutamate biosynthetic pathway in the brain. Cell. 2018; 173(7):1716-1727.e17. doi: 10.1016/j.cell.2018.04.014

[30] Zhang S, Zeng L, Ma J, et al. Gut prevotellaceae-GABAergic septohippocampal pathway mediates spatial memory impairment in high-fat diet-fed ovariectomized mice. Neurobiol Dis. 2023;177:105993. doi: 10.1016/j.nbd.2023.105993

[31] Li Y, Cheng Y, Zhou Y, et al. High fat diet-induced obesity leads to depressive and anxiety-like behaviors in mice via AMPK/mTOR-mediated autophagy. Exp Neurol. 2022;348:113949. doi: 10.1016/j.expneurol.2021.113949

[32] Ding N, Zhang X, Zhang XD, et al. Impairment of spermatogenesis and sperm motility by the high-fat diet-induced dysbiosis of gut microbes. Gut. 2020; 69(9):1608-1619. doi: 10.1136/gutjnl-2019-319127

[33] Sun P, Wang M, Li Z, et al. Eucommiae cortex polysaccharides mitigate obesogenic diet-induced cognitive and social dysfunction via modulation of gut microbiota and tryptophan metabolism. Theranostics. 2022; 12(8):3637-3655. doi: 10.7150/thno.72756

[34] Edgar RC. UPARSE: Highly accurate OTU sequences from microbial amplicon reads. Nat Methods. 2013; 10(10):996-998. doi: 10.1038/nmeth.2604

[35] Thackray VG. Sex, microbes, and polycystic ovary syndrome. Trends Endocrinol Metab. 2019; 30(1):54-65. doi: 10.1016/j.tem.2018.11.001

[36] Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature. 2011; 473(7346):174-180. doi: 10.1038/nature09944

[37] Dalile B, Kim C, Challinor A, et al. The EAT-Lancet reference diet and cognitive function across the life course. Lancet Planet Health. 2022; 6(9):e749-e759. doi: 10.1016/s2542-5196(22)00123-1

[38] Beam CR, Kaneshiro C, Jang JY, Reynolds CA, Pedersen NL, Gatz M. Differences between women and men in incidence rates of dementia and Alzheimer’s disease. J Alzheimers Dis. 2018; 64(4):1077-1083. doi: 10.3233/jad-180141

[39] Scheyer O, Rahman A, Hristov H, et al. Female sex and Alzheimer’s risk: The menopause connection. J Prev Alzheimers Dis. 2018; 5(4):225-230. doi: 10.14283/jpad.2018.34

[40] Zhang S, An X, Huang S, et al. AhR/miR-23a-3p/PKCα axis contributes to memory deficits in ovariectomized and normal aging female mice. Mol Ther Nucleic Acids. 2021; 24:79-91. doi: 10.1016/j.omtn.2021.02.015

[41] Gannon OJ, Robison LS, Salinero AE, et al. High-fat diet exacerbates cognitive decline in mouse models of Alzheimer’s disease and mixed dementia in a sex-dependent manner. 2022; 19(1):110. doi: 10.1186/s12974-022-02466-2

[42] Al-Azzawi F, Palacios S. Hormonal changes during menopause. Maturitas. 2009; 63(2):135-137. doi: 10.1016/j.maturitas.2009.03.009

[43] Lobo RA. Androgens in postmenopausal women: Production, possible role, and replacement options. Obstet Gynecol Surv. 2001; 56(6):361-376. doi: 10.1097/00006254-200106000-00022

[44] Sah SK, Lee C, Jang JH, Park GH. Effect of high-fat diet on cognitive impairment in triple-transgenic mice model of Alzheimer’s disease. Biochem Biophys Res Commun. 2017; 493(1):731-736. doi: 10.1016/j.bbrc.2017.08.122

[45] Szablewski L. Human gut microbiota in health and Alzheimer’s disease. J Alzheimers Dis. 2018; 62(2):549-560. doi: 10.3233/jad-170908

[46] Pan W, Zhao J, Wu J, et al. Dimethyl itaconate ameliorates cognitive impairment induced by a high-fat diet via the gut-brain axis in mice. Microbiome. 2023; 11(1):30. doi: 10.1186/s40168-023-01471-8

[47] Hooper LV, Midtvedt T, Gordon JI. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu Rev Nutr. 2002; 22:283-307. doi: 10.1146/annurev.nutr.22.011602.092259

[48] Gorvitovskaia A, Holmes SP, Huse SM. Interpreting Prevotella and Bacteroides as biomarkers of diet and lifestyle. Microbiome. 2016;4:15. doi: 10.1186/s40168-016-0160-7

[49] David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014; 505(7484):559-563. doi: 10.1038/nature12820

[50] Xue C, Li G, Zheng Q, et al. Tryptophan metabolism in health and disease. Cell Metab. 2023; 35(8):1304-1326. doi: 10.1016/j.cmet.2023.06.004

[51] Mauvais-Jarvis F, Clegg DJ, Hevener AL. The role of estrogens in control of energy balance and glucose homeostasis. Endocr Rev. 2013; 34(3):309-338. doi: 10.1210/er.2012-1055